Population Pharmacogenetics Group and Diabetes Research Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
Clin Pharmacol Ther. 2011 Feb;89(2):210-6. doi: 10.1038/clpt.2010.255. Epub 2010 Dec 22.
SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.
SLCO1B1 基因变异与严重的他汀类药物诱导的肌病有关。我们研究了这些变异是否也与接受他汀类药物作为常规临床治疗一部分的 2 型糖尿病患者的一般他汀类药物不耐受有关。共有 4196 名个体接受了 rs4149056（Val174Ala）和 rs2306283（Asp130Asn）的基因分型。不耐受通过血清生化和他汀类药物的停药、换药或剂量减少来定义。Ala174 与更高的不耐受相关（比值比=2.05，P=0.043），而 Asp130 与更低的不耐受相关（比值比=0.71，P=0.026）。Ala174 与他汀类药物降低低密度脂蛋白胆固醇（LDLc）的反应相关（P=0.01），而 130D 与他汀类药物降低 LDLc 的反应相关（P=0.048），如前所述；然而，当从分析中去除不耐受个体的数据时，这种关联不再存在。这项研究表明，选择他汀类药物诱导的肌病极端表型的常见遗传变异也易导致更常见的轻度他汀类药物不耐受，并且可能因此影响降脂效果。
